ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.313+1G>C
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(10); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.313+1G>C
Variation ID: 228358 Accession: VCV000228358.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11102787 (GRCh38) [ NCBI UCSC ] 19: 11213463 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 15, 2016 May 1, 2024 Aug 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.313+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195798.2:c.313+1G>C splice donor NM_001195799.2:c.191-2433G>C intron variant NM_001195800.2:c.313+1G>C splice donor NM_001195803.2:c.313+1G>C splice donor NM_001406861.1:c.572G>C NP_001393790.1:p.Arg191Pro missense NC_000019.10:g.11102787G>C NC_000019.9:g.11213463G>C NG_009060.1:g.18407G>C NG_140409.1:g.682G>C LRG_274:g.18407G>C LRG_274t1:c.313+1G>C - Protein change
- R191P
- Other names
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- Canonical SPDI
- NC_000019.10:11102786:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4017 | 4288 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2016 | RCV000213674.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 7, 2019 | RCV000844754.5 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Aug 30, 2023 | RCV001249083.10 | |
Pathogenic (3) |
criteria provided, single submitter
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Sep 29, 2022 | RCV001699015.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2023 | RCV002321838.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 7, 2023 | RCV003401129.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423040.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 04, 2022 |
Comment:
The c.313+1G>C variant in LDLR has been reported in at least 5 Spanish and/or Dutch individuals with familial hypercholesterolemia (PMID: 21935675, 7616128, 10790219), and has … (more)
The c.313+1G>C variant in LDLR has been reported in at least 5 Spanish and/or Dutch individuals with familial hypercholesterolemia (PMID: 21935675, 7616128, 10790219), and has been identified in 0.0009% (1/113710) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112029328). This variant has also been reported in ClinVar as both pathogenic and likely pathogenic (Variation ID: 228358). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. There is an in-frame cryptic splice site within 6 basepairs of the intron-exon boundary that could result in a rescued transcript and may maintain function of LDLR. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PS4_supporting (Richards 2015). (less)
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Pathogenic
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002576992.2
First in ClinVar: Oct 08, 2022 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more)
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22244043, 22390909, 25525159, 19318025, 21935675, 10790219, 11668640, 15241806, 31589614, 32660911, 34037665, 33087929, 7616128) (less)
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Pathogenic
(Jun 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002607712.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.313+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the LDLR gene. In silico splice … (more)
The c.313+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the LDLR gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in multiple familial hypercholesterolemia (FH) patients (Lombardi P et al. J Lipid Res. 1995;36:860-7; Mozas P et al. Hum Mutat. 2000;15:483-4; García-García AB et al. Hum Mutat. 2001;18:458-9). Two other alterations at the same nucleotide position, c.313+1G>A and c.313+1G>T, have also described in individuals with FH, and were shown to cause aberrant splicing as well as attenuated LDLR gene expression (Leren TP et al. Atherosclerosis. 1994;111:175-82; Jensen HK et al. Hum Mutat. 1996;7:269-71; Cameron J et al. Clin Chim Acta. 2009;403:131-5). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000294605.2
First in ClinVar: Jul 29, 2016 Last updated: May 19, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322889.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/208 non-FH alleles; 0/32 normolipidemic individuals; 0/60 healthy control individuals
Observation 1: Observation 2: |
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Pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503134.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1
Number of individuals with the variant: 1
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607444.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Jun 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271389.4
First in ClinVar: May 29, 2016 Last updated: Jul 03, 2020 |
Comment:
The c.313+1G>C variant in LDLR has been identified in >80 Spanish individuals with familial hypercholesterolemia (FH; Tejedor 2011). It has also been identified in 1/113710 … (more)
The c.313+1G>C variant in LDLR has been identified in >80 Spanish individuals with familial hypercholesterolemia (FH; Tejedor 2011). It has also been identified in 1/113710 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for FH in an autosomal dominant manner. PVS1_Strong, PS4, PM2. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001734548.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
This variant causes a G to C nucleotide substitution at the +1 position of intron 3 of the LDLR gene. Splice site prediction tools suggest … (more)
This variant causes a G to C nucleotide substitution at the +1 position of intron 3 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in more than 100 individuals affected with familial hypercholesterolemia (PMID: 10790219, 11668640, 15241806, 16627557, 19318025, 21935675, 22244043, 27784735, 30312929). This variant has been identified in 1/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511542.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: LDLR c.313+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: LDLR c.313+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes. c.313+1G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples: Mozas_2004, Alonso_2009). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Sevel submitters have classified the variant as likely pathogenic/pathogenic while one has classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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LDLR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105147.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The LDLR c.313+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in numerous individuals with … (more)
The LDLR c.313+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in numerous individuals with familial hypercholesterolemia (Lombardi et al. 1995. PubMed ID: 7616128; Mozas et al. 2000. PubMed ID: 10790219; García-García et al. 2001. PubMed ID: 11668640; Sánchez-Hernández et al. 2016. PubMed ID: 27784735). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11213463-G-C). Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003442662.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 228358). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 7616128). This variant is present in population databases (rs112029328, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 3 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). (less)
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Pathogenic
(Mar 01, 2016)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Iberoamerican FH Network
Accession: SCV000748173.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Chile
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963019.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606075.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921130.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
New contributions to the study of common double mutants in the human LDL receptor gene. | Tejedor MT | Die Naturwissenschaften | 2011 | PMID: 21935675 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Splice-site mutation c.313+1, G>A in intron 3 of the LDL receptor gene results in transcripts with skipping of exon 3 and inclusion of intron 3. | Cameron J | Clinica chimica acta; international journal of clinical chemistry | 2009 | PMID: 19361455 |
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis. | García-García AB | Human mutation | 2001 | PMID: 11668640 |
Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: identification of 3 novel mutations in the LDL receptor gene. | Mozas P | Human mutation | 2000 | PMID: 10790219 |
Two point mutations (313 + 1G --> A and 313 + 1G --> T) in the splice donor site of intron 3 of the low-density lipoprotein receptor gene are associated with familial hypercholesterolemia. | Jensen HK | Human mutation | 1996 | PMID: 8829662 |
Mutations in the low density lipoprotein receptor gene of familial hypercholesterolemic patients detected by denaturing gradient gel electrophoresis and direct sequencing. | Lombardi P | Journal of lipid research | 1995 | PMID: 7616128 |
Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects. | Leren TP | Atherosclerosis | 1994 | PMID: 7718019 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fecf6ec8-7608-4a29-a579-92f6aa3a9a2f | - | - | - | - |
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Text-mined citations for rs112029328 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.